Effects of chronic application of propranolol on beta-adrenergic signal transduction in heart ventricles from myopathic BIO TO2 and control hamsters.

1. In human congestive heart failure beta-adrenoceptor antagonists improve exercise tolerance and cardiac contractility. These beneficial effects are thought to reflect an up-regulation of cardiac beta-adrenoceptors, involving mainly the beta1-subtype. In the present study we evaluated the functional contribution of beta-adrenoceptor subtypes to stimulation of adenylyl cyclase in an animal model of dilated cardiomyopathy, and compared the effects of treatment with propranolol on cardiac beta-adrenergic signal transduction in myopathic and control hamsters. 2. Cardiomyopathic BIO TO2 hamsters and BIO F1B controls aged 270 days were used. In the treatment study, hamsters received drinking water with or without propranolol 40 mg kg(-1) d(-1) for 4 weeks prior to sacrifice. Density and subtype distribution of beta-adrenoceptors were determined in radioligand binding studies. Functional contributions of beta-adrenoceptors were evaluated by subtype-selective stimulation of adenylyl cyclase. Cardiac G-protein content was determined by immunoblotting. 3. Compared to BIO F1B controls, myopathic hamsters showed increases in cardiac total beta- and beta2-adrenoceptor density, G(s alpha) and G(i alpha) content. In BIO TO2 ventricles, beta1-adrenoceptors were almost completely uncoupled from adenylyl cyclase stimulation despite an unchanged density. Treatment of hamsters with propranolol resulted in increased density of beta1-adrenoceptors in both strains, but had no effect on their functional efficacy. Moreover, beta2-adrenergic stimulation of adenylyl cyclase was even reduced in propranolol-treated animals, which could not be explained by changes in cardiac G-protein content. 4. Cardiomyopathic BIO TO2 hamsters showed functional uncoupling of cardiac beta1-adrenoceptors, which could not be normalized by propranolol and, therefore, is unlikely to be solely due to agonist-dependent desensitization. The paradoxical reduction in beta2-adrenergic efficiency in propranolol-treated myopathic and control hamsters deserves further investigation.